1. Field of the Invention
The present invention relates to a process for producing (R)-3-hydroxy-4-butyrolactone from its enantiomer (S)-3-hydroxy-4-butyrolactone.
2. Description of the Background
Both (S)-3-hydroxy-4-butyrolactone, 1(S), and (R)-3-hydroxy-4-butyrolactone, 1(R), are versatile chiral intermediates useful in several industrial synthesis. Lactone 1(S) is e.g. utilised in the preparation of (S)-oxyracetam, esters of 5,6-dihydroxy-3-ketohexanol and natural-like substances, such as multistriatine. IT 01276207 (Sigma-Tau) discloses a process for producing 1(S) from (S)-carnitine, a cheap waste compound which forms in the preparation of (R)-carnitine (of which several therapeutical utilisations are known) in equimolar amounts with respect to (R)-carnitine. Indeed, the processes most widely utilised to-date for preparing (R)-carnitine are based on the resolution of racemic mixtures. Also EP 513,430 discloses a process for preparing 1(S) from, however, a source of D-hexoses.
The lactone 1(R) can be used for synthesizing .beta.-lactame antibiotics, the known anticonvulsivant GABOB [(R)-4-amino-3-hydroxybutyric acid] and (R)-carnitine. In order to carry out the (R)-carnitine synthesis, lactone 1(R) is first converted to an alkyl-4-halogen-3-hydroxybutyrate (as disclosed e.g. in JP 04149151) which is then converted to (R)-carnitine (see e.g. Zhou, B.; Gopalan, A. S.; Van Meddlesworth, F.; Shieh, W. R.; Sih, C. J., J. Am. Chem. Soc. 1983, 105, 5925-5926; Boots, S. G; Boots, M. R.; J. Pharm. Science, 1975, 64, 1262-1264).
In spite of its utility as a versatile intermediate, to-date no satisfactorily suitable processes have been provided which allow an industrial scale synthesis to be conducted.
The synthesis from L-ascorbic acid is a 7-step process and its yield is 29% only (Tanaka, A.; Yamashita, K, Synthesis, 1987, 570-572), whilst the synthesis from dimethyl-(R)-malate requires a cumbersome reduction step with the borane-dimethylsulfide complex and NaBH.sub.4. This reduction step is practically unfeasible on an industrial scale and entails severe safety and pollution problems (Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.; Moriwake, T., Chem. Lett., 1984,1389-1392).
It would be, therefore, advantageous to have an industrially feasible process for producing (R)-3-hydroxy-4-butyrolactone, which does not present the several serious drawbacks of the known methods: a plurality of steps, low yields, unsatisfactory optical purity, use of expensive, hazardous and/or polluting reactants.
The object of the present invention is to provide such a process which further present the advantage of utilizing the enantiomer of the end compound, i.e. (S)-3-hydroxy-4-butyrolactone, as starting material which, as previously mentioned, can be easily and unexpensively obtained from a waste material such as (S)-carnitine with the process disclosed in IT 01276207.
The process of the present invention is shown in the following reaction scheme: ##STR1##
With reference to the previous reaction scheme, the process of the present invention comprises the steps of:
(1) acylating (S)-3-hydroxy-4-butyrolactone, 1(S), to (S)-3-acyloxy-4-butyrolactone, 2(S), wherein --OR is a leaving group wherein R is a group selected from alkylsulfonyl having 1-12 carbon atoms, arylsulfonyl, formyl and trifluoroacetyl, by reacting 1(S) with an acylating agent selected from an acyl halogenide RY and an anhydride R--O--R wherein Y is halogen, preferably chlorine, and R is as previously defined, optionally in the presence of an organic base consisting of a tertiary amine, in an aprotic organic solvent, at molar ratio 1(S):acylating agent:organic base from 1:1:1 to 1:5:5, or in a basic solvent, at molar ratio 1(S):acylating agent from 1:1 to 1:5, at 10-70.degree. C., for 1-24 hours; PA1 (2) hydrolysing 2(S) in an aqueous environment with an acidic resin, for 1-24 hours, thus obtaining (S)-3-acyloxy-4-hydroxybutyric acid, 3(S); PA1 (3) converting 3(S) to (R)-3-hydroxymethyl-3-propiolactone 4(R) by treating 3(S) with a base; and PA1 (4) converting 4(R) to (R)-3-hydroxy-4-butyrolactone 1(R) in a basic environment and then acidifying to pH 3-0, or directly in an acid environment at pH 3-0, at 10-100.degree. C., for 1-24 hours.
As regards the acylating step (1), the acylating agent is preferably an alkylsulfonyl having 1-4 carbon atoms. Mesyl is the particularly preferred alkylsulfonyl.
The organic base is preferably selected from the group consisting of pyridine, trimethylamine, lutidine and picoline and the organic aprotic solvent is selected from the group consisting of acetonitrile, chloroform and methylene chloride.
According to the preferred embodiment, the acylation is carried out at molar ratio 1(S):acylating agent:organic base of 1:1.5:1.5, at room temperature, for 5 hours.
In step (2), the acidic resin is preferably a strongly acidic resin selected from the group consisting of AMBERLITE IR 120 and AMBERLIST 15. Isolation of the resulting (S)-3-acyloxy-4-hydroxybutyric acid is not necessary.
In step (3) wherein 3(S) is converted to lactone 4(R) the treatment of 3(S) with a base is preferably carried out with an inorganic base selected from the group consisting of NaHCO.sub.3, Na.sub.2 CO.sub.3 and NaOH or an organic base selected from the group consisting of trimethylamine and pyridine at 10-80.degree. C.
The lactone 4(R), (R)-3-hydroxymethyl-3-propiolactone, is a novel compound. In step (4), the conversion of 4(R) to the final lactone 1(R) is preferably carried out by alkaline hydrolysis with 3N NaOH for 30-60 minutes, preferably 45 minutes, at room temperature, and subsequent acidification with 3N HCl to pH 2 or by acidification, preferably with 2N HCl.